Work led by St. Jude Children’s Research Hospital investigators provides fresh insight into mechanisms controlling programmed cell death pathways and offers new targets in the fight against cancer and virus-infected cells
Work led by St. Jude Children’s Research Hospital scientists identified how cells flip a switch between cell survival and cell death that involves a protein called FLIP.
The findings solve a riddle that has puzzled scientists for more than a decade regarding the dual nature of caspase-8, an enzyme intimately linked to the cell’s suicide pathway but also essential for cell survival during embryonic development and the immune response. Researchers identified FLIP and the silencing of another enzyme, named RIPK3, as playing pivotal roles. The study was published in the March 2 advance online edition of Nature.
Douglas Green, Ph.D., the paper’s senior author and chair of the St. Jude Department of Immunology, said work is already underway to use the findings to generate new cancer treatment targets and fresh insight into the missteps that give rise to certain tumors as well as evidence of how some virus-infected cells escape the pathways designed to dispatch such threats.
“It is a pretty rare thing to ‘cure’ a lethal mutation in an animal by removing another gene. When that happens, the biology shouts out to us that this is important. We just have to listen,” Green said.
FLIP’s role was identified after investigators bred mice that lacked genes for both caspase-8 and RIPK3. Previous research identified RIPK3 as responsible for orchestrating cell death via programmed necrosis. Once viewed as an uncontrolled form of cell death, programmed necrosis is now recognized as a distinct form of cell suicide. The body relies on both programmed necrosis and apoptosis, the more common process, to rid itself of damaged, dangerous or unneeded cells.
While loss of caspase-8 was known to be lethal during embryonic development, in this study investigators showed mice that lacked both caspase-8 and RIPK3 were born at normal rates and appeared developmentally normal early in life.
Investigators went on to show that caspase-8 prevents programmed necrosis by combining with FLIP to form an enzyme complex that disrupts RIPK3 functioning and so prevents death via programmed necrosis. The work also demonstrated that FLIP expression prevents caspase-8 from triggering cell death via apoptosis, although the exact mechanism must still be determined. Apoptosis relies on caspase enzymes and other molecules to ensure the cell self destructs.
Green said the findings provide insight into the mechanisms at work in neuroblastoma and other tumors that suffer a loss of caspase-8. “We are beginning collaborative experiments to examine these tumors to see if RIPK3 is deleted or blocked,” he said. Neuroblastoma arises in cells of the sympathetic nervous system. It is the most common solid tumor in children, accounting for up to 10 percent of all childhood cancers.
Andrew Oberst, a St. Jude postdoctoral fellow, is the study’s first author. The other authors are Christopher Dillon, Ricardo Weinlich, Laura McCormick and Patrick Fitzgerald, all of St. Jude; Cristina Pop and Guy Salvesen, of Sanford-Burnham Medical Research Institute, La Jolla; and Razq Hakem, of the University of Toronto.
The research was supported in part by the National Institutes of Health, the Canadian Institutes of Health Research, the Sass Foundation for Medical Research and ALSAC.St. Jude Children’s Research Hospital
Founded in 1962 by the late entertainer Danny Thomas, St. Jude freely shares its discoveries with scientific and medical communities around the world, publishing more research articles than any other pediatric cancer research center in the United States. St. Jude treats more than 5,700 patients each year and is the only pediatric cancer research center where families never pay for treatment not covered by insurance. St. Jude is financially supported by thousands of individual donors, organizations and corporations without which the hospital’s work would not be possible. For more information, go to www.stjude.org.St. Jude Public Relations Contacts:
Summer Freeman | Newswise Science News
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy